tbuckley/cabot-search huggingface dataset:
Novel peptide-based vaccine targeting heat shock protein 90 induces effective antitumor immunity in a HER2+ breast cancer murine model
Authors: Jinho Kang, Hye-Jin Lee, Jimin Lee, Jinhwa Hong, Yeul Hong Kim, Mary L Disis, Jeong-An Gim, Kyong Hwa Park
Journal: Journal for ImmunoTherapy of Cancer (2022)

Heat shock protein 90 (HSP90) is a protein chaperone for most of the important signal transduction pathways in human epidermal growth factor receptor 2-positive (HER2+) breast cancer, including human epidermal growth factor receptor 2, estrogen receptor, progesterone receptor and Akt. The aim of our study is to identify peptide-based vaccines and to develop an effective immunotherapeutics for the treatment of HER2+ breast cancer. HSP90-derived major histocompatibility complex (MHC) class II epitopes were selected using in silico algorithms and validated by enzyme-linked immunospot (ELISPOT). In vivo antitumor efficacy was evaluated in MMTVneu-transgenic mice. HSP90 peptide-specific systemic T-cell responses were assessed using interferon gamma ELISPOT assay, and immune microenvironment in tumors was evaluated using multiplex immunohistochemistry and TCRβ sequencing. First, candidate HSP90-derived MHC class II epitopes with high binding affinities across multiple human HLA class II genotypes were identified using in silico algorithms. Among the top 10 peptides, p485 and p527 were selected as promising Th1 immunity-inducing epitopes with low potential for Th2 immunity induction. The selected MHC class II HSP90 peptides induced strong antigen-specific T cell responses, which was induced by cross-priming of CD8+ T cells in vivo. The HSP90 peptide vaccines were effective in the established tumor model, and their efficacy was further enhanced when combined with stimulator of interferon genes (STING) agonist and/or anticytotoxic T lymphocyte-associated antigen-4 antibody in MMTVneu-transgenic mice. Increased tumor rejection was associated with increased systemic HSP90-specific T-cell responses, increased T-cell recruitment in tumor microenvironment, intermolecular epitope spreading, and increased rearrangement of TCRβ by STING agonist. In conclusion, we have provided the first preclinical evidence of the action mechanism of HSP90 peptide vaccines with a distinct potential for improving breast cancer treatment.
Is covid-19 settling into a pattern?
Authors: Mun-Keat Looi
Journal: BMJ (2022)

SARS-CoV-2 is here to stay, with an increasing array of questions for science and medicine. In the first of a new series on Covid Unanswered Questions, <b>The BMJ</b> asks about our current understanding of waves and variants—and what they might mean for “living with the virus”
Driving adult tissue repair via re-engagement of a pathway required for fetal healing
Authors: Subhadip Ghatak, Savita Khanna, Sashwati Roy, Mahesh Thirunavukkarasu, Seetur R. Pradeep, Brian C. Wulff, Mohamed S. El Masry, Anu Sharma, Ravichand Palakurti, Nandini Ghosh, Yi Xuan, Traci A. Wilgus, Nilanjana Maulik, Mervin C. Yoder, Chandan K. Sen
Journal: Molecular Therapy (2022)

Fetal cutaneous wound closure and repair differ from that in adulthood. In this work, we identify an oxidant stress sensor protein, nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase (NPGPx), that is abundantly expressed in normal fetal epidermis (and required for fetal wound closure), though not in adult epidermis, but is variably re-induced upon adult tissue wounding. NPGPx is a direct target of the miR-29 family. Following injury, abundance of miR-29 is lowered, permitting a prompt increase in NPGPx transcripts and protein expression in adult wound-edge tissue. NPGPx expression was required to mediate increased keratinocyte migration induced by miR-29 inhibition in vitro and in vivo. Increased NPGPx expression induced increased SOX2 expression and β-catenin nuclear localization in keratinocytes. Augmenting physiologic NPGPx expression via experimentally induced miR-29 suppression, using cutaneous tissue nanotransfection or targeted lipid nanoparticle delivery of anti-sense oligonucleotides, proved to be sufficient to overcome the deleterious effects of diabetes on this specific pathway to enhance tissue repair.
Targeted genomic translocations and inversions generated using a paired prime editing strategy
Authors: Jiyeon Kweon, Hye-Yeon Hwang, Haesun Ryu, An-Hee Jang, Daesik Kim, Yongsub Kim
Journal: Molecular Therapy (2022)

A variety of cancers have been found to have chromosomal rearrangements, and the genomic abnormalities often induced expression of fusion oncogenes. To date, a pair of engineered nucleases including ZFNs, TALENs, and CRISPR-Cas9 nucleases have been used to generate chromosomal rearrangement in living cells and organisms for disease modeling. However, these methods induce unwanted indel mutations at the DNA break junctions, resulting in incomplete disease modeling. Here, we developed prime editor nuclease-mediated translocation and inversion (PETI), a method for programmable chromosomal translocation and inversion using prime editor 2 nuclease (PE2 nuclease) and paired pegRNA. Using PETI method, we successfully introduced DNA recombination in episomal fluorescence reporters as well as precise chromosomal translocations in human cells. We applied PETI to create cancer-associated translocations and inversions such as NPM1-ALK and EML4-ALK in human cells. Our findings show that PETI generated chromosomal translocation and inversion in a programmable manner with efficiencies comparable of Cas9. PETI methods, we believe, could be used to create disease models or for gene therapy.
A pilot randomized controlled trial on the utility of gastric conditioning in the prevention of esophagogastric anastomotic leak after Ivor Lewis esophagectomy. The APIL_2013 Trial
Authors: Kristel Mils, Mònica Miró, Leandre Farran, Sebastian Videla, Esther Alba, Fernando Estremiana, Carla Bettonica, Humberto Aranda
Journal: International Journal of Surgery (2022)
Crafting ɣ-L-Glutamyl-l-Cysteine layered Human Serum Albumin-nanoconstructs for brain targeted delivery of ropinirole to attenuate cerebral ischemia/reperfusion injury via “3A approach”
Authors: Saman Fatima, Mubashshir Ali, Syed Naved Quadri, Sarwar Beg, M. Samim, Suhel Parvez, Malik Zainul Abdin, Prashant Mishra, Farhan Jalees Ahmad
Journal: Biomaterials (2022)
Targeting FoxO transcription factors with HDAC inhibitors for the treatment of osteoarthritis
Authors: Hiroki Ohzono, Yiwen Hu, Keita Nagira, Haruhisa Kanaya, Naoki Okubo, Merissa Olmer, Masafumi Gotoh, Ichiro Kurakazu, Yukio Akasaki, Manabu Kawata, Emily Chen, Alan C Chu, Kristen A Johnson, Martin K Lotz
Journal: Annals of the Rheumatic Diseases (2022)

Osteoarthritis (OA) features ageing-related defects in cellular homeostasis mechanisms in articular cartilage. These defects are associated with suppression of forkhead box O (FoxO) transcription factors. FoxO1 or FoxO3 deficient mice show early onset OA while FoxO1 protects against oxidative stress in chondrocytes and promotes expression of autophagy genes and the essential joint lubricant proteoglycan 4 (PRG4). The objective of this study was to identify small molecules that can increase FoxO1 expression.
Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy: efficacy and safety results of a randomised controlled phase III study
Authors: Eugen Feist, Saeed Fatenejad, Sergey Grishin, Elena Korneva, Michael E Luggen, Evgeniy Nasonov, Mikhail Samsonov, Josef S Smolen, Roy M Fleischmann
Journal: Annals of the Rheumatic Diseases (2022)

To assess the efficacy and safety of olokizumab (OKZ), a monoclonal antibody against the interleukin-6 (IL-6) cytokine, versus placebo (PBO) in patients with prior inadequate response to tumour necrosis factor inhibitors (TNFi-IRs).In this 24-week multicentre, placebo-controlled, double-blind study, the patients were randomised in a 2:2:1 ratio to receive subcutaneously administered OKZ 64 mg once every 2 weeks (q2w), OKZ 64 mg once every 4 weeks (q4w) or PBO plus methotrexate. At week 16, the patients on PBO were randomised to receive either OKZ regime. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. Disease Activity Score 28-joint count C-reactive protein (DAS28 (CRP))<3.2 at week 12 was the major secondary efficacy endpoint. Safety and immunogenicity were assessed.In 368 patients randomised, ACR20 response rates were 60.9% in OKZ q2w, 59.6% in OKZ q4w and 40.6% in PBO (p<0.01 for both comparisons). Achievement of DAS28 (CRP) <3.2 was significantly different, favouring the OKZ arms. Improvements in efficacy and patient-reported outcomes were maintained throughout 24 weeks and were noted after week 16 in patients who switched from PBO.Dose-related treatment-emergent serious adverse events were 7% in OKZ q2w, 3.2% in OKZ q4w and none in the PBO group.Direct inhibition of IL-6 with OKZ resulted in significant improvements in the signs and symptoms of rheumatoid arthritis compared with PBO in TNF-IR patients with a similar safety profile as observed for monoclonal antibodies to the IL-6 receptor.NCT02760433.
Safety and immunogenicity of a third COVID-19 vaccination in patients with immune-mediated inflammatory diseases compared with healthy controls
Authors: Felix Kartnig, Daniel Mrak, Elisabeth Simader, Selma Tobudic, Helga Radner, Peter Mandl, Lisa Göschl, Nikolaus Hommer, Margareta Mayer, Philipp Hofer, Thomas Hummel, Thomas Deimel, Irina Geßl, Antonia Puchner, Andreas Kerschbaumer, Renate Thalhammer, Alessandra Handisurya, Renate Kain, Stefan Winkler, Josef S Smolen, Karin Stiasny, Thomas Perkmann, Helmuth Haslacher, Judith H Aberle, Daniel Aletaha, Leonhard X Heinz, Daniela Sieghart, Michael Bonelli
Journal: Annals of the Rheumatic Diseases (2022)

Objectives A third COVID-19 vaccination is recommended for immunosuppressed patients. However, data on immunogenicity and safety of a third COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMIDs) are sparse and therefore addressed within this clinical trial. Methods 60 immunosuppressed patients and 48 healthy controls (HCs) received a third vaccination with an mRNA vaccine. The primary endpoint was defined as the presence of antibody levels against the receptor-binding domain (RBD)&gt;1500 BAU/mL in patients with IMIDs versus HCs. Further endpoints included differences in neutralising antibodies and cellular immune responses after the third vaccination. Reactogenicity was recorded for 7 days, and safety was evaluated until week 4. Results Rate of individuals with anti-RBD antibodies&gt;1500 BAU/mL was not significantly different after the third vaccination between patients with IMIDs and HCs (91% vs 100% p=0.101). Anti-RBD and neutralising antibody levels were significantly lower in patients with IMIDs after the third vaccination than in HCs (p=0.002 and p=0.016, respectively). In contrast, fold increase in antibody levels between week 0 and 4 was higher in patients with IMIDs. Treatment with biological (b) disease-modifying anti-rheumatic drugs (DMARD) or combination of bDMARDs and conventional synthetic DMARDs was associated with reduced antibody levels. Enhanced cellular immune response to wild type and Omicron peptide stimulation was observed after the third vaccination. No serious adverse event was attributed to the third vaccination. Conclusion Our clinical trial data support the immunogenicity and safety of a third COVID-19 vaccination in patients with IMIDs. However, effects of DMARD therapy on immunogenicity should be considered. Trial registration number EudraCT No: 2021-002693-10.
Reciprocal interaction between vascular niche and sweat gland promotes sweat gland regeneration
Authors: Xingyu Yuan, Xianlan Duan, None Enhejirigala, Zhao Li, Bin Yao, Wei Song, Yuzhen Wang, Yi Kong, Shijun Zhu, Fanliang Zhang, Liting Liang, Mengde Zhang, Chao Zhang, Deling Kong, Meifeng Zhu, Sha Huang, Xiaobing Fu
Journal: Bioactive Materials (2022)

The incorporation of vasculature is known to be effective in tissue or organ functional regeneration. However, a vague understanding of the interaction between epidermal appendages and their vascular niches is a foremost obstacle to obtaining sweat gland (SG)-specific vasculature units. Here, we map their precise anatomical connections and report that the interplay between SG cells (SGCs) and the surrounding vascular niche is key for glandular development and homeostasis maintenance. To replicate this interplay in vitro, we used three-dimensional (3D) bioprinting to generate reproducible SGC spheroids from differentiated adipose-derived mesenchymal stem cells (ADSCs). With dermal microvascular endothelial cells (DMECs), sacrificial templates made from poly (ε-caprolactone) (PCL) were fabricated to pattern the vascular niche. This interplay model promoted physiologically relevant vascularized glandular morphogenesis in vitro and in vivo. We identified a reciprocal regulatory mechanism for promoting SGs regeneration via contact-independent cell communication and direct cell-cell interactions between SGs and the vasculature. We envision the successful use of our approach for vascularized organ regeneration in the near future.
Genome editing in cancer: Challenges and potential opportunities
Authors: Dor Breier, Dan Peer
Journal: Bioactive Materials (2022)

Ever since its mechanism was discovered back in 2012, the CRISPR/Cas9 system have revolutionized the field of genome editing. While at first it was seen as a therapeutic tool mostly relevant for curing genetic diseases, it has been recently shown to also hold the potential to become a clinically relevant therapy for cancer. However, there are multiple challenges that must be addressed prior to clinical testing. Predominantly, the safety of the system when used for in-vivo therapies, including off-target activity and the effects of the double strand break induction on genomic stability. Here, we will focus on the inherent challenges in the CRISPR/Cas9 system and discuss various opportunities to overcoming these challenges.
Safety, tolerability, and immunogenicity of a 21-valent pneumococcal conjugate vaccine, V116, in healthy adults: phase 1/2, randomised, double-blind, active comparator-controlled, multicentre, US-based trial
Authors: Heather Platt, Tosin Omole, Jose Cardona, Neil J Fraser, Richard A Mularski, Charles Andrews, Nizar Daboul, Nancy Gallagher, Aditi Sapre, Jianing Li, Adam Polis, Doreen Fernsler, Gretchen Tamms, Weifeng Xu, Rocio Murphy, Julie Skinner, Joseph Joyce, Luwy Musey
Journal: The Lancet Infectious Diseases (2022)
OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy
Authors: Sofia Ahola, Pablo Rivera Mejías, Steffen Hermans, Srikanth Chandragiri, Patrick Giavalisco, Hendrik Nolte, Thomas Langer
Journal: Cell Metabolism (2022)

Cardiomyopathy and heart failure are common manifestations in mitochondrial disease caused by deficiencies in the oxidative phosphorylation (OXPHOS) system of mitochondria. Here, we demonstrate that the cardiac-specific loss of the assembly factor Cox10 of the cytochrome c oxidase causes mitochondrial cardiomyopathy in mice, which is associated with OXPHOS deficiency, lysosomal defects, and an aberrant mitochondrial morphology. Activation of the mitochondrial peptidase Oma1 in Cox10−/− mice results in mitochondrial fragmentation and induction of the integrated stress response (ISR) along the Oma1-Dele1-Atf4 signaling axis. Ablation of Oma1 or Dele1 in Cox10−/− mice aggravates cardiomyopathy. ISR inhibition impairs the cardiac glutathione metabolism, limits the selenium-dependent accumulation of the glutathione peroxidase Gpx4, and increases lipid peroxidation in the heart, ultimately culminating in ferroptosis. Our results demonstrate a protective role of the Oma1-Dele1-mediated ISR in mitochondrial cardiomyopathy and link ferroptosis to OXPHOS deficiency and mitochondrial disease.
Spike mutation resilient scFv76 antibody counteracts SARS-CoV-2 lung damage upon aerosol delivery
Authors: Ferdinando M. Milazzo, Antonio Chaves-Sanjuan, Olga Minenkova, Daniela Santapaola, Anna M. Anastasi, Gianfranco Battistuzzi, Caterina Chiapparino, Antonio Rosi, Emilio Merlo Pich, Claudio Albertoni, Emanuele Marra, Laura Luberto, Cécile Viollet, Luigi G. Spagnoli, Anna Riccio, Antonio Rossi, M. Gabriella Santoro, Federico Ballabio, Cristina Paissoni, Carlo Camilloni, Martino Bolognesi, Rita De Santis
Journal: Molecular Therapy (2022)

The uneven worldwide vaccination coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and emergence of variants escaping immunity call for broadly effective and easily deployable therapeutic agents. We have previously described the human single-chain scFv76 antibody, which recognizes SARS-CoV-2 Alpha, Beta, Gamma and Delta variants. We now show that scFv76 also neutralizes the infectivity and fusogenic activity of the Omicron BA.1 and BA.2 variants. Cryoelectron microscopy (cryo-EM) analysis reveals that scFv76 binds to a well-conserved SARS-CoV-2 spike epitope, providing the structural basis for its broad-spectrum activity. We demonstrate that nebulized scFv76 has therapeutic efficacy in a severe hACE2 transgenic mouse model of coronavirus disease 2019 (COVID-19) pneumonia, as shown by body weight and pulmonary viral load data. Counteraction of infection correlates with inhibition of lung inflammation, as observed by histopathology and expression of inflammatory cytokines and chemokines. Biomarkers of pulmonary endothelial damage were also significantly reduced in scFv76-treated mice. The results support use of nebulized scFv76 for COVID-19 induced by any SARS-CoV-2 variants that have emerged so far. The uneven worldwide vaccination coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and emergence of variants escaping immunity call for broadly effective and easily deployable therapeutic agents. We have previously described the human single-chain scFv76 antibody, which recognizes SARS-CoV-2 Alpha, Beta, Gamma and Delta variants. We now show that scFv76 also neutralizes the infectivity and fusogenic activity of the Omicron BA.1 and BA.2 variants. Cryoelectron microscopy (cryo-EM) analysis reveals that scFv76 binds to a well-conserved SARS-CoV-2 spike epitope, providing the structural basis for its broad-spectrum activity. We demonstrate that nebulized scFv76 has therapeutic efficacy in a severe hACE2 transgenic mouse model of coronavirus disease 2019 (COVID-19) pneumonia, as shown by body weight and pulmonary viral load data. Counteraction of infection correlates with inhibition of lung inflammation, as observed by histopathology and expression of inflammatory cytokines and chemokines. Biomarkers of pulmonary endothelial damage were also significantly reduced in scFv76-treated mice. The results support use of nebulized scFv76 for COVID-19 induced by any SARS-CoV-2 variants that have emerged so far.
Response of primary tumor and lymph node in non-small cell lung cancer after neoadjuvant immunotherapy: a pooled analysis
Authors: Wen-Yu Zhai, Ze-Rui Zhao, Si Chen, Hui Yu, Yao-Bin Lin, Yi-Zhi Wang, Hao Long
Journal: Journal for ImmunoTherapy of Cancer (2022)

The good pathological response of primary tumors (PTs) to neoadjuvant immunotherapy has been acknowledged in non-small cell lung cancer (NSCLC), however, it remains unclear whether neoadjuvant immunotherapy shows consistent effects in metastatic lymph nodes (LNs). We compared the pathological response of PT and nodal downstaging using a pooled analysis to assess the effect of neoadjuvant immunotherapy on LNs. Original articles reporting the tumor major pathological response (ypT(MPR)), pathological complete response (ypT0) and nodal downstaging following neoadjuvant immunotherapy in NSCLC were retrieved. The OR and 95% CI were calculated by Review Manager V.5.3. Subgroup analysis was performed according to the neoadjuvant therapy regimen used. A total of 209 patients from 6 studies were included in this analysis. The frequency of nodal downstaging was comparable to that of ypT(MPR) (OR 1.31; 95% CI 0.84 to 2.05; p=0.24). Interestingly, ypN0 was observed more frequently than ypT0 (OR 3.26; 95% CI 2.06 to 5.16; p&lt;0.0001). However, this difference was not observed in the subgroup of cN2 patients who underwent immune checkpoint inhibitor monotherapy (OR 1.58; 95% CI 0.56 to 4.48; p=0.39). Neoadjuvant immunotherapy results in satisfactory response in metastatic LN. Patients had a high probability of node clearance when ypT0 was confirmed, especially in patients treated with immunochemotherapy.
Analyses of rare predisposing variants of lung cancer in 6,004 whole genomes in Chinese
Authors: Cheng Wang, Juncheng Dai, Na Qin, Jingyi Fan, Hongxia Ma, Congcong Chen, Mingxing An, Jing Zhang, Caiwang Yan, Yayun Gu, Yuan Xie, Yuanlin He, Yue Jiang, Meng Zhu, Ci Song, Tao Jiang, Jia Liu, Jun Zhou, Nanxi Wang, Tingting Hua, Shuang Liang, Lu Wang, Jing Xu, Rong Yin, Liang Chen, Lin Xu, Guangfu Jin, Dongxin Lin, Zhibin Hu, Hongbing Shen
Journal: Cancer Cell (2022)
Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity
Authors: Agnieszka Chryplewicz, Julie Scotton, Mélanie Tichet, Anoek Zomer, Ksenya Shchors, Johanna A. Joyce, Krisztian Homicsko, Douglas Hanahan
Journal: Cancer Cell (2022)
Using Natural Language Processing to Automatically Identify Dysplasia in Pathology Reports for Patients With Barrett’s Esophagus
Authors: Theresa Nguyen Wenker, Yamini Natarajan, Kadon Caskey, Francisco Novoa, Nabil Mansour, Huy Anh Pham, Jason K. Hou, Hashem B. El-Serag, Aaron P. Thrift
Journal: Clinical Gastroenterology and Hepatology (2022)
Genetic polymorphisms in MIR1208 and MIR5708 are associated with susceptibility to COPD in the Chinese population
Authors: Y. Zhou, F. Bai, X. Li, G. Zhou, X. Tian, G. Li, Y. Zhang, X. Zhou, D. Xu, Y. Ding
Journal: Pulmonology (2022)

Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by limited airflow and is influenced by genetic and environmental factors. The purpose of this study was to investigate the effects of gene polymorphisms in MIR5708 and MIR1208 on COPD risk. Four single nucleotide polymorphisms (SNPs) in MIR5708 (rs6473227 and rs16907751) and MIR1208 (rs2608029 and rs13280095) were selected and genotyped among 315 COPD patients and 314 healthy controls using the Agena MassARRAY platform. SPSS 18.0 was used for statistical analysis and data processing. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the association between genetic variants of MIR1208 and MIR5708 and COPD risk. The results suggested that rs16907751 variants in MIR5708 contributed to an increased susceptibility to COPD in the allelic (P = 0.001), co-dominant (homozygous) (P = 0.001), dominant (P = 0.017), recessive (P = 0.002), and additive (P = 0.002) models. The effects of MIR5708 and MIR1208 gene polymorphisms on the risk of COPD were age-, sex-, smoking status-, and BMI-related. Furthermore, the C-A and G-A haplotypes of rs2608029 and rs13280095 in MIR1208 were identified as risk factors for COPD in the population over 70 years (P = 0.029) and in women (P = 0.049), respectively. Finally, significant associations between rs16907751genotypes with pulse rate and forced expiratory volume in 1 s were found among COPD patients. Genetic polymorphisms in MIR5708 and MIR1208 are associated with increased risk of COPD in China.